Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder condition characterized by urinary frequency, urgency, and pelvic pain. The etiology and pathogenesis of IC/PBS are still unclear despite extensive investigation. Whereas local bladder-related factors contributing to this illness have been examined, little is known regarding underlying systemic conditions that might permit a state of chronic inflammation and pain to be established and maintained in IC/PBS. Findings from animal models indicate that the responses of the hypothalamic pituitary adrenal (HPA) axis to inflammatory mediators influence susceptibility to inflammatory illnesses. Abnormalities of the HPA feedback system result in poorer regulation of the inflammatory response and are present in many chronic inflammatory and pain conditions, some of which some have high comorbidity with IC/PBS. These include irritable bowel syndrome (IBS) and fibromyalgia (FM). The high levels of comorbidity between these conditions and IC/PBS suggest that similar pathophysiological mechanisms may be operating in IC/PBS. HPA abnormalities, however, have not been systematically investigated in IC/PBS. The main objectives of this project are to: 1) investigate the characteristics of subgroups of IC/PBS patients based on presence/absence of comorbid diagnoses such as IBS and FM, 2) examine dysregulations of the HPA axis and inflammation in IC/PBS patients with and without comorbid diagnoses, and 3) examine the relationship of the HPA axis and inflammation to symptoms in IC/PBS patients. We hypothesize that the HPA axis is involved in the pathophysiology of the chronic inflammation observed in IC/PBS and that there are subgroups of IC/PBS patients with different patterns of HPA dysfunction. We also hypothesize that interactions between cortisol and bladder mast cells and other inflammatory mediators may contribute to IC/PBS symptomatology. To test these hypotheses, the integrity of the HPA axis and levels of inflammatory mediators will be assessed at rest and when challenged in a standardized laboratory stress reactivity protocol. We plan to use a 4-group design: IC/PBS patients with no comorbid conditions; 2) IC/PBS patients with comorbid fibromyalgia (FM) or irritable bowel syndrome (IBS); 3) patients with functional somatic syndromes (patients with FM or IBS with no IC/PBS); and healthy controls.